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Definitions

• the invention relates to derivatives of 5-alkyloxy-indolin-2-one, their method of production and their therapeutic applications. These novel derivatives have affinity and selectivity for the V 2 receptors of vasopressin (“V 2 receptors”) and can therefore constitute active principles of pharmaceutical compositions.
• V 2 receptors vasopressin
• Vasopressin is a hormone that is known for its antidiuretic effect and its effect in the regulation of arterial pressure. It stimulates several types of receptors: V 1 (V 1a , V 1b or V 3 ), V 2 .
• Oxytocin has a peptide structure similar to that of vasopressin.
• V 1 (V 1a , V 1b ), V 2 and OXT receptors are localised in common tissues and organs (Jard S. et al., “Vasopressin and oxytocin receptors: an overview in progress” in Endocrinology, Himura H. and Shizume K ed., or in: Pharmacol. Rev., 1991 43 (1), 73-108).
• the aim of the present invention is to find novel compounds having potent selectivity for the V 2 vasopressin receptors, while displaying good pharmacological properties.
• the compounds according to the invention notably display good metabolic stability, making them particularly suitable for use as a medicinal product.
• the inventors have developed a new family of compounds having affinity and selectivity for the V 2 vasopressin receptors. These novel compounds are potent antagonists of binding of the V 2 vasopressin receptors. Moreover, the compounds of formula (I) according to the invention display good metabolic stability, notably on human hepatic microsomes, thus confirming the advantages of these compounds for use as medicinal products.
• the invention relates to the compounds of general formula (I) hereunder:
• R 0 represents a (C 1 -C 4 )alkyl group, a mono or polyfluoro-(C 1 -C 4 )alkyl group, a (CH 2 ) n -cyclopropyl group,
• R 1 represents a hydrogen atom, a (C 1 -C 5 )alkyl group, a mono or polyfluoro-(C 1 -C 5 )alkyl group, a hydroxy-(C 1 -C 5 )alkyl group, a —(CH 2 ) m —(C 3 -C 5 )cycloalkyl group;
• Z 1 represents a hydrogen atom or halogen atom, a (C 1 -C 4 )alkyl group, a mono or polyfluoro-(C 1 -C 4 )alkyl group, a (C 1 -C 4 )alkoxy group, a mono or polyfluoro-(C 1 -C 4 )alkoxy group, a —(CH 2 ) p -cyclopropyl group, said cyclopropyl group being unsubstituted or substituted with one or more fluorine atoms;
• Z 2 represents a halogen atom or a group T 1 W, in which T 1 represents a group —(CH 2 ) n — and W represents a hydrogen atom, a (C 1 -C 4 )alkyl group, mono or polyfluoro-(C 1 -C 4 )alkyl group or a cyclopropyl group unsubstituted or substituted with one or more fluorine atoms,
• R 4 represents a (C 1 -C 4 )alkyl group, a mono or polyfluoro-(C 1 -C 4 )alkyl group, an —OR, (C 2 -C 4 ) alkenyl, nitro, COOR c , a benzyloxy group,
• R 3 and R 5 represent, independently of one another, a hydrogen atom, a halogen atom, a (C 1 -C 4 )alkyl group, a mono or polyfluoro-(C 1 -C 4 )alkyl group, a (C 1 -C 4 )alkoxy or mono or polyfluoro-(C 1 -C 4 )alkoxy group;
• R a and R b represent, independently of one another:
• R′ and R represent, independently of one another, a hydrogen atom, a (C 1 -C 4 )alkyl group or mono or polyfluoro-(C 1 -C 4 )alkyl group;
• R c represents a hydrogen atom, a (C 1 -C 4 )alkyl group, mono or polyfluoro-(C 1 -C 4 )alkyl group or a benzyl group;
• R d and R e represent, independently of one another, a hydrogen, atom, a halogen atom, a (C 1 -C 6 )alkyl group or mono or polyhalogen-(C 1 -C 6 )alkyl group,
• n can represent the value 0, 1 or 2;
• n can represent the value 0 or 1;
• p can represent the value 0, 1, 2 or 3;
• q can represent the value 2, 3, 4 or 5;
• r can represent the value 0, 1, 2, 3 or 4;
• s can represent the value 1, 2 or 3.
• the compounds of general formula (I) can occur in the form of tautomers.
• the invention relates to the compounds of the invention in all their tautomeric forms.
• the compounds of general formula (I) can have one or more asymmetric carbon atoms. They can therefore be in the form of enantiomers or of diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, form part of the invention.
• the compounds of general formula (I) can contain double bonds or one or more saturated rings. They can therefore be in the form of cis/trans isomers. These isomers, and mixtures thereof, form part of the invention.
• the compounds of general formula (I) can occur as bases or acids and salts of addition. Said salts of addition form part of the invention.
• salts are advantageously prepared with pharmaceutically acceptable acids or bases, but the salts of other acids or bases that can be used, for example, for purifying or isolating the compounds of general formula (I) also form part of the invention.
• the compounds of general formula (I) can be in the form of hydrates or of solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Said hydrates and solvates also form part of the invention.
• the N-oxides of the compounds bearing an amine also form part of the invention.
• the compounds of formula (I) according to the present invention also include those in which one or more atoms of hydrogen, carbon or halogen, notably of chlorine or of fluorine have been replaced by their radioactive isotopes, for example tritium to replace hydrogen or carbon 14 to replace carbon 12.
• Said labelled compounds are useful in research, in studies of metabolism or of pharmacokinetics, and in biochemical assays as ligands of receptors.
• prodrugs of the compounds of formula (I) according to the present invention also form part of the invention.
• prodrugs we mean compounds that are metabolised in vivo to compounds of the invention. Examples of prodrugs are described notably in John B. Taylor (Vol. Ed): Comprehensive Medicinal Chemistry, Pergamon Press, 1990, Vol. 5 p. 122-132 and in C. Wermuth (Ed.): The Practice of Medicinal Chemistry, Elsevier Academic Press, 2003, p. 561-585.
• prodrugs we may mention compounds in which a —COO(C 1 -C 6 )alkyl ester group, a —OC(O)R group or an amino group in which one or two hydrogens are replaced by (C 1 -C 6 )alkyl groups are the prodrugs of compound (I) according to the invention, containing respectively a —COOH carboxylic acid group, an —OH alcohol group or a primary amine group —NH 2 .
• the compounds of the invention according to (I) can themselves behave in vivo as prodrugs of other compounds of the invention according to (I).
• an aminocarbonyl group —C(O)NR 6 R 7 , R 6 and R 7 being defined as previously and can lead to a compound (I) according to the invention having a —COOH group.
• C 1 -C 3 represents a carbon chain that can have from 1 to 3 carbon atoms
• the present invention also relates to methods of preparation of the compounds of general formula (I).
• the compounds of the invention can be prepared by the methods shown in the schemes given below, the operating conditions of which are conventional for a person skilled in the art.
• Protecting group PG means a group that is able to prevent the reactivity of a function or position, during a chemical reaction that might affect it, and that restores the molecule after cleavage according to methods known by a person skilled in the art.
• Temporary protecting groups of amines or alcohols means the protecting groups such as those described in Protective Groups in Organic Synthesis, Greene T. W. and Wuts P. G. M., Ed. Wiley Intersciences 1999 and in Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag.
• temporary protecting groups of the amines benzyls, carbamates (such as tert-butyloxycarbonyl groups that can be cleaved in an acid environment, benzyloxycarbonyl groups that can be cleaved by hydrogenolysis), temporary protecting groups of carboxylic acids: alkyl esters (such as methyl or ethyl, tert-butyl hydrolysable in a basic or acid medium) and hydrogenolysable benzyl esters, temporary protecting groups of alcohols or of phenols such as the tetrahydropyranyl, methyloxymethyl or methylethoxymethyl, tert-butyl and benzyl ethers, temporary protecting groups of carbonylated derivatives such as the linear or cyclic acetals, for example 1,3-dioxan-2-yl or 1,3-dioxolan-2-yl; and reference may be made to the well-known general methods described in Protective Groups,
• the compounds of formula (I) can include groups that are precursors of other functions that are generated subsequently in one or more other stages.
• Leaving group means, hereinafter, a group that can easily be cleaved by heterolytic bond rupture; we may mention for example the halogens (I, Br, CI, F) or an activated hydroxyl group such as a methanesulphonate, benzenesulphonate, p-toluenesulphonate, triflate, acetate, etc.
• halogens I, Br, CI, F
• an activated hydroxyl group such as a methanesulphonate, benzenesulphonate, p-toluenesulphonate, triflate, acetate, etc.
• Precursor group means, hereinafter, any group that can be transformed in one or more stages to another group by the chemical reactions known by a person skilled in the art.
• R 0 represents a (C 1 -C 3 )alkyl group, in particular methyl, the other groups being as defined for the compound of general formula (I).
• R 0 represents a (C 1 -C 3 )alkyl group, in particular methyl
• R 1 represents a (C 1 -C 5 )alkyl group, the other groups being as defined for the compound of general formula (I).
• R 0 represents a methyl group
• R 1 represents a (C 1 -C 2 )alkyl group, more particularly ethyl, the other groups being as defined for the compound of general formula (I).
• Z 1 represents a halogen atom, more particularly a fluorine atom or a chlorine atom, the other groups being as defined for the compound of general formula (I).
• R 4 represents a group —C(O)NR 13 R 14 , in which R 13 , R 14 and the other groups are as defined for the compound of general formula (I).
• Z 2 represents a group T 1 W, in which T 1 represents a group —(CH 2 ) n — with n equal to 0 and W represents a group —OR 12 in which R 12 represents a hydrogen atom.
• Patient means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.
• Treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
• “Therapeutically effective amount” means a quantity of the compound which is effective in treating the named disorder or condition.
• “Pharmaceutically acceptable carrier” is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
• a pharmaceutically acceptable oil typically used for parenteral administration.
• the compounds of general formula (I) can be obtained according to Scheme 1 hereunder.
• the compounds of formula (I) are obtained by reaction of a compound of formula (II) with a compound of formula (III).
• X represents a halogen atom and the groups R′ 3 , R′ 4 and R′ 5 represent respectively, and independently of one another, the groups R 3 , R 4 and R 5 as defined for the compound of formula (I) or precursor groups of groups R 3 , R 4 and R 5 .
• groups R′ 0 , R′ 1 , Z′ 1 and Z′ 2 represent respectively, and independently of one another, the groups R 0 , R 1 , Z 1 and Z 2 as defined for the compound of formula (I) or precursor groups of groups R 0 , R 1 , Z 1 and Z 2 .
• the compounds of formula (I) are obtained directly by reaction of a compound of formula (II) with a compound of formula (III) when the groups R′ 0 , R′ 1 , R′ 3 , R′ 4 , R′ 5 , Z′ 1 and Z′ 2 represent respectively the groups R 0 , R 1 , R 3 , R 4 , R 5 , Z 1 and Z 2 as defined for the compound of formula (I).
• the compounds of formula (I) are obtained indirectly via a compound of formula (I′) when at least one of the groups R′ 0 , R′ 1 , R′ 3 , R′ 4 , R′ 5 , Z′ 1 and Z′ 2 represents respectively a precursor group of the groups R′ 0 , R 1 , R 3 , R 4 , R 5 , Z 1 and Z 2 as defined for the compound of formula (I).
• a compound of formula (II) is carried out in the presence of a metal hydride, for example sodium hydride, or of an alkaline alcoholate, for example potassium tert-butylate at temperatures between ⁇ 40° and 25° C., in an anhydrous solvent such as tetrahydrofuran (THF).
• a metal hydride for example sodium hydride
• an alkaline alcoholate for example potassium tert-butylate
• the compounds of formula (I′) can also represent compounds of formula (I).
• the conversion of the precursor groups R′ 0 , R′ 1 , Z′ 1 , Z′ 2 , R′ 3 , R′ 4 and R′ 5 respectively, and independently of one another, to groups R′ 0 , R′ 1 , Z′ 1 , Z 2 , R 3 , R 4 and R 5 as defined, is achieved according to general, conventional techniques that are well known by a person skilled in the art, for example by reactions of alkylation, acylation, oxidation or reduction.
• the compounds of formula (III) can be prepared by the reaction of a compound of formula (IV) in which R′ 1 , Z′ 1 and 12 are as defined for the compound of formula (III), in the presence of a base such as an alkaline alcoholate, potassium tert-butylate for example, with a derivative R′ 0 —Z in which R′ 0 is as defined for the compound of formula (III) and Z represents a leaving group such as an iodine or a bromine or alternatively a sulphonate such as mesylate or tosylate, in an anhydrous solvent such as DMF or THF at temperatures between ⁇ 40° C. and 20° C.
• a base such as an alkaline alcoholate, potassium tert-butylate for example
• the compounds of formula (III) can be obtained from the compounds of formula (VI)— in which R′ 1 , R′ 0 , Z′ 1 and Z′ 2 are as defined for the compounds of formula (III) and R′′ represents a (C 1 -C 3 )alkyl group—by cyclization of the amine of formula (VI′)—in which R′ 1 , R′ 0 , Z′ 1 and Z′ 2 are as defined for the compounds of formula (III) and R′′ represents a (C 1 -C 3 )alkyl group—generated in situ during reduction of the nitro group carried by the compound of formula (VI).
• This is carried out in the presence of a metal in an acid environment, such as tin or iron in an acid environment such as acetic acid at temperatures between 30 and 100° C.
• the compounds of formula (IV) can be obtained by reduction of compounds derived from 3-hydroxy-indolin-2-one by reacting tin chloride in an acid environment, by analogy with the method described in Tetrahedron Letters 1996, 52 (20), 7003-7012 or Bioorganic and Medicinal Chemistry Letters 1997, 7 (10), 1255-1260.
• R′ 1 , Z′ 1 and Z′ 2 are as defined for the compounds of formula (III).
• the 3-hydroxy-indolin-2-one derivatives are known or prepared from isatins that are commercially available or are known, by reaction with an organometallic derivative such as an organolithium or an organomagnesium compound according to, for example Biorg. Med. Lett. 7 (10); 1997; 1255.
• organometallic derivative such as an organolithium or an organomagnesium compound according to, for example Biorg. Med. Lett. 7 (10); 1997; 1255.
• the compounds of formula (IV) can also be obtained by the methods described notably in document WO01/74775 (page 19, lines 16 to 25 and page 20, lines 1, 2).
• a strong base such as an alkaline alcoholate, potassium tert-butylate or sodium hydride for example, in an anhydrous solvent such as DMF.
• N-oxides of the compounds bearing an amine are prepared according to methods known by a person skilled in the art by reaction of the amine with organic peracids such as peracetic, trifluoroperacetic, performic, perbenzoic acids or derivatives thereof such as 3-chloroperbenzoic acid, at temperatures between 0° C. and 90° C., preferably at temperatures below 50° C.
• organic peracids such as peracetic, trifluoroperacetic, performic, perbenzoic acids or derivatives thereof such as 3-chloroperbenzoic acid
• the pure enantiomers of the compounds of the invention can be prepared from enantiomerically pure precursors or alternatively by chiral phase chromatography or, when the compounds bear acid functions or amines, by selective crystallization of diastereoisomeric salts obtained by reaction of compounds (I) with, respectively, chiral amines or acids.
• m.p. melting point (in degrees Celsius) measured on a Kofler bench
• the rotatory power [ ⁇ ]D/20 is measured on a PERKIN-ELMER 241 polarimeter in standard conditions, at a temperature of 20° C.; the concentration c is expressed in g of solute per 100 ml of solution.
• Enantiomeric resolution of the preceding compound prepared in C) is carried out by supercritical chiral-phase chromatography in the following conditions:
• the expected product is obtained in the form of powder.
• the expected product is obtained in the form of crystals.
• the expected product is obtained in the form of powder.
• the expected product is obtained in the form of powder.
• the expected product is obtained in the form of powder.
• Enantiomeric resolution of the preceding acid is performed by supercritical chiral-phase chromatography in the following conditions:
• the expected product is obtained in the form of a beige powder.
• Enantiomeric resolution of the preceding compound prepared in C) is performed by supercritical chiral-phase chromatography in the following conditions:
• Enantiomeric resolution of the 3-(2-chlorophenyl)-5-ethoxy-3-ethyl-1,3-dihydroindol-2-one is carried out by supercritical chiral-phase chromatography under the following conditions: Equipment: Berger Prep SFC supercritical chromatography system with Pronto software. Chiral column: CHIRALPAK AD-H 5 ⁇ m, length: 25 cm, diameter: 21 mm
• Me denotes a methyl group
• Et denotes an ethyl group
• Pr denotes an n-propyl group
• Bn denotes a benzyl group.
• N-tert-Butyl-4-[3-(2-chloro-phenyl)-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-indole-1-sulphonyl]-3-methoxybenzamide is obtained in a similar way to Example 2, from laevorotatory 3-(2-chloro-phenyl)-5-ethoxy-3-methyl-1,3-dihydro-indol-2-one (Preparation
• N-tert-Butyl-4-[3-(2-fluoro-phenyl)-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-indole-1-sulphonyl]-benzamide is obtained in a similar way to Example 5 from laevorotatory 3-(2-fluoro-phenyl)-5-ethoxy-3-methyl-1,3-dihydro-indol-2-one (Preparation 5).
• Example 20 From 3-[1-(4-tert-Butylcarbamoyl-2-methoxy-benzenesulphonyl)-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-chloro-benzoic acid (Example 19) and the preceding amine (stage A of Example 45), we obtain the desired compound in the form of a white powder.
• Example 20 From 3-[1-(4-tert-butylcarbamoyl-2-methoxy-benzenesulphonyl)-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-chloro-benzoic acid (Example 19) and 1-methyl-octahydro-pyrrolo[3,4-b]pyrrole obtained according to the conditions described in “Justus Liebigs Ann. Chemie 677, 154 (1964)”, we obtain the desired compound in the form of a white powder.
• hydrochloride of the desired compound is obtained in the form of a white powder by deprotection of the preceding compound in an ethereal solution of hydrochloric acid.
• N-tert-butyl-4- ⁇ 3-[2-chloro-5-(3-pyridylmethylaminocarbonyl)phenyl]-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-indole-1-sulphonyl ⁇ benzamide is obtained in the conditions of Example 20, from 3-[1-(4-tert-butylcarbamoyl-benzenesulphonyl)-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-chloro-benzoic acid (Example 48) and 3-pyridylmethylamine.
• N-tert-butyl-4-[3-(2-chloro-5-pyrrolidin-1-ylmethyl-phenyl)-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-indole-1-sulphonyl]-3-methoxy-benzamide is obtained in the same way as in Example 5, from the compound prepared previously (stage A of Example 63).
• the hydrochloride of the desired compound is obtained in the form of a white powder by deprotection of the compound of Example 67 in an ethereal solution of hydrochloric acid.
• Example 48 Under conditions similar to Example 92, the examples given in Table IX below are obtained starting from 3-[1-(4-tert-butylcarbamoylbenzenesulphonyl)-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-chlorobenzoic acid (Example 48) and appropriate commercially available alcohols.
• the compounds of the invention underwent pharmacological testing, which demonstrated their advantages as active substances in therapeutics.
• the affinity of the compounds of the invention for the V 2 vasopressin receptors was determined in an in vitro binding test, by the procedure described below.
• Plasma membranes (about 20 ⁇ g/ml) obtained from CHO tissue or cell line expressing human recombinant V 2 vasopressin receptors, are incubated for 45 minutes at 25° C. in 200 ⁇ L of TRIS-HCl buffer (50 mM; pH 8.2) containing 2 mM of MgCl 2 , 1 mM of EDTA, 0.1% of BSA, 1/500 protease inhibitor cocktail (Sigma #P2714) and 3.5 nM of [H3]-AVP. The reaction is stopped by filtration and washing on GF/B filters. Nonspecific binding is determined in the presence of 1 ⁇ M of AVP.
• the compounds of the invention dissolved beforehand to a concentration of 10 ⁇ 2 M in DMSO, are tested in a dilution series.
• IC 50 concentration of product inhibiting 50% of specific binding
• Biost@t-SPEED v1.3 which employs the 4-parameter logistic model of Ratkovsky and Reedy (1986). Adjustment is obtained by nonlinear regression using Marquardt's algorithm of the SAS v8.2 software running under UNIX.
• the affinity of the compounds according to the invention for the OXT receptors was determined in an in vitro binding test using the method described by J. Elands et al. in Eur. J. Pharmacol. 1987, 147, 197-207. This method comprises in vitro investigation of the displacement of a radioiodated analogue of oxytocin from the oxytocin receptors in a membrane preparation of human oxytocin receptors.
• the affinity of the compounds according to the invention for human V ia receptors was determined according to the method described by M. Thibonnier et al. in J. Biol. Chem. 1994, 269, 3304-3310.
• the affinity of the compounds according to the invention for the V 1b receptors was determined according to the method described by T. Sugimoto et al. in J. Biol. Chem. 1994, 269, 27088-27092.
• the compounds of the present invention have high affinity and selectivity for the V 2 vasopressin receptors.
• the affinities measured on the V 1a , V 1b and OXT receptors were compared with that measured on the V 2 receptor in Table A above. It is considered that when the IC 50 values are greater than 1 ⁇ M (1000 nM), the compounds have little affinity for the receptor tested.
• the selectivity of the compounds according to the invention for the V 2 receptor can be demonstrated by the ratios calculated between the different values of IC 50 measured on each receptor and the IC 50 measured on the V 2 receptor: the higher this ratio, the higher the selectivity of the compounds according to the invention for the V 2 receptors.
• the IC 50 ratios of the compounds according to the invention are much higher than 10, thus demonstrating their selectivity.
• the compounds according to the invention having affinity and selectivity for the V 2 receptors, display good pharmacological properties and are particularly suitable for use in the preparation of medicinal products, especially of medicinal products that are antagonists of binding to the V 2 receptors.
• the invention therefore relates to medicinal products that comprise at least one compound of formula (I).
• V 2 vasopressin receptors display aquaretic properties in animals and humans ( Cardiovascular Drug Review , (2001), 3: pp. 201-214).
• the compounds according to the invention possess a broad range of therapeutic indications and can advantageously replace conventional diuretics in all the pathologies where they are recommended for humans and animals.
• the compounds according to the invention may be useful notably in the treatment and/or prevention of disorders of the central and peripheral nervous systems, of the cardiovascular system, of the endocrine and hepatic system, of the renal system, of the gastric, intestinal and pulmonary system, in opthalmology and in problems of sexual behaviour, in humans and in animals.
• the compounds according to the invention can be used in the treatment and/or prevention of various vasopressin-dependent disorders as well as in dysfunction of vasopressin secretion such as the inappropriate syndrome of secretion of vasopressin (or “SIADH”, for Syndrome of Inappropriate ADH Secretion), cardiovascular disorders, such as hypertension, pulmonary hypertension, heart failure, circulatory failure, myocardial infarction, atherosclerosis or coronary vasospasm, especially in smokers, unstable angina and percutaneous transluminal coronary angioplasty (PTCA), ischaemic heart disease, disturbances of haemostasis notably haemophilia, Von Willebrand syndrome; central nervous system disorders, pain, migraine, cerebral vasospasm, cerebral haemorrhage, cerebral oedema, depression, anxiety, bulimia, psychotic, states, for example memory problems; renopathies and renal dysfunction such as oedema, renal vasospasm, necrosis of the renal cortex,
• the compounds according to the invention can also be used in the treatment and/or prevention of problems of sexual behaviour, in overweight conditions or excess weight and obesity, advantageously replacing the conventional diuretics already used for this indication.
• compounds according to the invention can be used for treating dysmenorrhoea or premature labour.
• the compounds according to the invention can also be used in the treatment of small cell lung cancers, hyponatraemic encephalopathies, Raynaud disease, pulmonary syndrome, glaucoma and prevention of cataract, in postoperative treatments, notably after abdominal, cardiac or haemorrhagic surgery and in treatments of disorders or diseases of the inner ear such as Méley disease, tinnitus, vertigo, hearing difficulties, notably for low tones, or buzzing, hydrops and notably endolymphatic hydrops, osteoporosis.
• the present invention relates to pharmaceutical compositions comprising, as active principle, at least one compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound of formula (I) according to the invention, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are selected according to the dosage form and the desired method of administration, from the usual excipients that are known by a person skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or any salt, solvate or hydrate thereof, can be administered in a unit dosage form, mixed with conventional pharmaceutical excipients, to animals and to human beings for the prophylaxis or treatment of the aforementioned disorders or diseases.
• the appropriate unit dosage forms comprise the oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular, intranasal administration or administration by inhalation, forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, forms for rectal administration and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unit dosage form of a compound according to the invention in the form of a tablet can comprise the following components:
• Said unit forms are dosed to provide a daily administration from 0.5 mg to 800 mg of active principle per individual, more particularly from 0.5 mg to 200 mg, depending on the galenical form.
• the appropriate dosage for each patient is determined by the doctor according to the method of administration, and said patient's weight and response.
• the present invention also relates to a method of treatment and/or prevention of the aforementioned pathologies, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or of one of its hydrates or solvates.

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